Acute lymphoblastic leukemia (ALL) is the most prevalent cancer among children and adolescents less than 15 years of age. Central nervous system (CNS) treatment with intrathecal and intravenous methotrexate is an essential part of ALL therapy because the brain is a sanctuary site for leukemia cells. Despite the importance of CNS treatment for long-term disease-free survival, declines in academic abilities, especially math and reading have been reported. Our preliminary findings demonstrate declines in specific cognitive abilities during the first two years of CNS treatment, while declines in academic abilities are evident after 3 years of treatment. Early changes in specific cognitive abilities may be important predictors of academic outcomes. Methotrexate increases oxidative stress in several organs, including the brain. White matter and the hippocampus are known to be vulnerable to oxidative stress, and are important for cognitive abilities, such as working memory, learning, visual-spatial and visual-motor skills. Oxidative stress as a mechanism of methotrexate-induced CNS injury that may lead to cognitive declines and academic outcomes has not been studied. The long-term goal is to increase knowledge about mechanisms of methotrexate-induced CNS injury, and to develop interventions that will prevent or minimize tissue damage, cognitive declines, and academic problems that are significant challenges for long-term survivors of childhood ALL. The purpose is to explicate relationships among oxidative stress, cognitive abilities, and academic outcomes among children with ALL who receive aggressive CNS treatment with methotrexate. Specific Aims are to: 1. Describe changes in oxidative stress during CNS treatment with methotrexate. 2. Describe changes in cognitive abilities during CNS treatment with methotrexate. 3. Describe relationships among oxidative stress, cognitive abilities, and academic outcomes. A prospective longitudinal design enrolling 80 children with ALL between 3 and 12 years of age will be used. Verbal and non-verbal cognitive abilities will be assessed within 1 month after diagnosis, and then annually for 3 years. Academic abilities will be assessed 3 years after ALL diagnosis. CSF samples will be obtained during diagnostic and therapeutic lumbar punctures for measuring oxidative stress. Aims 1 and 2 will be addressed using mixed model ANOVAs. Aim 3 will be addressed using correlations and multiple regression. Ancillary analyses will be conducted to describe the potential influence of covariates (total amount of methotrexate received, subject gender and age, and maternal education) on oxidative stress, cognitive abilities, and academic outcomes. This is the first study of oxidative stress as a mechanism of methotrexate-induced CNS injury that could be associated with early declines in cognitive abilities and academic outcomes among children with ALL. Findings will provide the basis for future studies of biological and cognitive interventions designed to prevent or minimize CNS tissue injury, and improve cognitive abilities and academic outcomes among the ever increasing number of long-term survivors of childhood leukemia. Public Health Relevance: Acute leukemia is the most common cancer among children in the United States. Curative therapy requires treating the brain with chemotherapy which frequently results in devastating effects on learning, academic abilities and employment opportunities for leukemia survivors. This study will increase knowledge about how chemotherapy damages normal brain tissue, and determine if this damage leads to the cognitive and academic problems experienced by children with leukemia.